Comparative molecular dynamics—Similar folds and similar motions?

Pang, Andrew; Arinaminpathy, Yalini; Sansom, Mark S. P.; Biggin, Philip C.

doi:10.1002/prot.20672

Cited by 49 publications

(57 citation statements)

References 74 publications

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“…These motions can occur concurrently. This has been observed before for this class of protein (30,31); thus, we are reasonably confident that this motion is genuine. Although subdomain closure has been observed before in simulations of these and other proteins (31,32) and evidence suggests that the ligand-binding domain exists in an open/closed equilibrium in the apo state (33), we are cautious not to overinterpret this motion.…”

Section: Resultssupporting

confidence: 88%

“…This has been observed before for this class of protein (30,31); thus, we are reasonably confident that this motion is genuine. Although subdomain closure has been observed before in simulations of these and other proteins (31,32) and evidence suggests that the ligand-binding domain exists in an open/closed equilibrium in the apo state (33), we are cautious not to overinterpret this motion. The simulation of the ligand-binding domain in the absence of the rest of the subunit may have led to a higher likelihood of a closure event caused by the lack of an opposing force that would be provided by the transmembrane ion channel domain.…”

Section: Resultssupporting

confidence: 88%

“…The Open-Apo transition and the general motion of the trajectories as decomposed by the eigenvector analysis reveals the principal motions of the ligand-binding core to be a lobe twisting motion and a hinge motion in agreement with previous observations (30,31). The speed of the closing transition observed during the Open-Apo simulation is fast (nanosecond time scale) and is currently beyond the resolution of experimental techniques for single molecules.…”

Section: Tablesupporting

confidence: 86%

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Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

Kaye¹,

Sansom²,

Biggin³

2006

Journal of Biological Chemistry

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The mechanism of partial agonism at N-methyl-D-aspartate receptors is an unresolved issue, especially with respect to the role of protein dynamics. We have performed multiple molecular dynamics simulations (7 ؋ 20 ns) to examine the behavior of the ligand-binding core of the NR1 subunit with a series of ligands. Our results show that water plays an important role in stabilizing different conformations of the core and how a closed cleft conformation of the protein might be stabilized in the absence of ligands. In the case of ligand-bound simulations with both full and partial agonists, we observed that ligands within the binding cleft may undergo distinct conformational changes, without grossly influencing the degree of cleft closure within the ligand-binding domain. In agreement with recently published crystallographic data, we also observe similar changes in backbone torsions corresponding to the hinge region between the two lobes for the partial agonist, D-cycloserine. This observation rationalizes the classification of D-cycloserine as a partial agonist and should provide a basis with which to predict partial agonism in this class of receptor by analyzing the behavior of these torsions with other potential ligands. N-Methyl-D-aspartate (NMDA)4 receptors are ligand-gated ion channels that play a major role in learning and memory (1). They have also been implicated in a number of injury or disease states including for example, schizophrenia (2-5). NMDA receptors are a distinct subtype of ionotropic glutamate receptor (6) in that they require both glutamate and glycine for activation and membrane depolarization (7). The receptor is a heterotetrameric cation channel typically comprised of two NR1 subunits that contain the glycine-binding site along with two NR2A-D glutamate-binding sites. The heterogeneity of the complex is further extended if the third subtype (NR3), which also binds glycine, is also taken into account.The architecture of each subunit of NMDA receptors is similar to that of non-NMDA receptors. Each subunit is comprised of an aminoterminal binding domain that shows homology to the LIVBP (leucineisoleucine-valine-binding protein) (8), three transmembrane helices (M1, M2, and M3), a re-entrant P-loop, and a ligand-binding domain that is comprised of two discontinuous polypeptide chains, S1 and S2, that form two distinct lobes or subdomains, D1 and D2 (Fig. 1A). An isolated D1D2 ligand-binding core has been shown to bind ligands with similar affinity as wild-type receptors (9, 10).Recently, the crystal structure of the ligand-binding domain of the NR1 subunit has been solved by x-ray diffraction with both full (9) and partial (10) agonists. The overall fold and structure (Fig. 1B) is very similar to those observed for crystal structures of the ligand-binding domains for the (non-NMDA) GluR2 (11-13), GluR5 (14,15), and GluR6 receptors (Refs. 15 and 16; for recent reviews see Refs. 17-19). The major difference is an insertion of 30 residues into loop 1, which also contains two disulfide bridges. Inter...

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Section: Resultssupporting

confidence: 88%

Section: Resultssupporting

confidence: 88%

Section: Tablesupporting

confidence: 86%

See 1 more Smart Citation

Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

Kaye¹,

Sansom²,

Biggin³

2006

Journal of Biological Chemistry

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“…Thus, the simulation has provided details of a pathway for subdomain closure within the GluR2 ligand-binding domain. Although this motion occurs on a relatively fast timescale (on the order of nanoseconds) our observations of similar motions across a range of proteins possessing this fold (Pang et al, 2003(Pang et al, , 2005 gives us confidence that this motion is functionally relevant.…”

Section: Figmentioning

confidence: 72%

“…Counter-ions were positioned such that they were in bulk solvent. From previous comparative studies (Pang et al, 2005) in which several similar proteins from this fold family were simulated and compared, we are confident that positioning in this way is not critical to the overall dynamics of the protein. All systems were energy minimized and subjected to a short (200 ps) restrained molecular dynamics run in which the protein (and ligand if present) heavy atoms were restrained by an harmonic force of 1000 kJ mol Ϫ1 nm Ϫ2 .…”

Section: Methodsmentioning

confidence: 84%

Binding Site Flexibility: Molecular Simulation of Partial and Full Agonists within a Glutamate Receptor

Arinaminpathy¹,

Sansom²,

Biggin³

2005

Mol Pharmacol

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Ionotropic glutamate receptors mediate fast synaptic transmission in the mammalian central nervous system and play an important role in many different functions, including memory and learning. They have also been implicated in a variety of neuropathologies and as such have generated widespread interest in their structure and function. Molecular Dynamics simulations (5 ϫ 20 ns) of the ligand-binding core of the GluR2 glutamate receptor were performed. Through simulations of both wild type and the L650T mutant, we show that the degree of protein flexibility can be correlated with the extent to which the binding cleft is open. In agreement with recent experiments, the simulations of kainate with the wild-type construct show a slight increase in ␤-sheet content that we are able to localize to two specific regions. During one simulation, the protein made a transition from an open-cleft conformation to a closed-cleft conformation. This closed cleft conformation closely resembles the closed-cleft crystal structure, thus indicating a potential pathway for conformational change associated with receptor activation. Analysis of the binding pocket suggests that partial agonists possess a greater degree of flexibility within the pocket that may help to explain why they are less efficient at opening the channel than full agonists. Examination of water molecules surrounding the ligands reveals that mobility in distinct subsites can be a discriminator between full and partial agonism and will be an important consideration in the design of drugs against these receptors.The ionotropic glutamate receptors (iGluR) receptors are a family of ligand-gated ion-channels that open in response to the binding of glutamate and are responsible for fast excitatory neurotransmission in vertebrate central nervous systems. In humans, dysfunction of iGluRs has been implicated in a variety of neuropathologies (Dingledine et al., 1999). iGluRs have been classified according to their sequences and the pharmacology of their responses to a variety of ligands (Holman and Heinemann, 1994). Those receptors (GluR1-4) that show greatest sensitivity to the agonist ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) are termed AMPA receptors (Borges and Dingledine, 1998). Likewise, those that show greatest sensitivity to kainate (GluR5-7, KA1-2) are referred to as kainate receptors (Lerma et al., 1997;Chittajallu et al., 1999). Receptors that are activated by N-methyl-D-aspartate (NMDAR1, NMDAR2a-d) are called NMDA receptors (Yamakura and Shimoji, 1999). In vivo, NMDA receptors require both glutamate and glycine to bind for activation.The overall architecture of iGluR consists of two extracellular domains and a transmembrane (TM) domain. The ligand-binding domain, the crystal structure of which is known (Armstrong et al., 1998), forms the second extracellular domain. It is made up of two polypeptide segments (called S1 and S2) that discontinuously form the two subdomains (or lobes) referred to as D1 and D2 (Fig. 1). The transmembrane domain i...

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Parallel dynamics and evolution: Protein conformational fluctuations and assembly reflect evolutionary changes in sequence and structure

Marsh

Teichmann

2013

BioEssays

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Protein structure is dynamic: the intrinsic flexibility of polypeptides facilitates a range of conformational fluctuations, and individual protein chains can assemble into complexes. Proteins are also dynamic in evolution: significant variations in secondary, tertiary and quaternary structure can be observed among divergent members of a protein family. Recent work has highlighted intriguing similarities between these structural and evolutionary dynamics occurring at various levels. Here we review evidence showing how evolutionary changes in protein sequence and structure are often closely related to local protein flexibility and disorder, large-scale motions and quaternary structure assembly. We suggest that these correspondences can be largely explained by neutral evolution, while deviations between structural and evolutionary dynamics can provide valuable functional insights. Finally, we address future prospects for the field and practical applications that arise from a deeper understanding of the intimate relationship between protein structure, dynamics, function and evolution.

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Comparative molecular dynamics—Similar folds and similar motions?

Cited by 49 publications

References 74 publications

Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

Binding Site Flexibility: Molecular Simulation of Partial and Full Agonists within a Glutamate Receptor

Parallel dynamics and evolution: Protein conformational fluctuations and assembly reflect evolutionary changes in sequence and structure

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